Implantable device

ABSTRACT

A device for implanting in the body. The device comprises a chamber containing cells. The device also comprises an oxygen generator for providing oxygen to the cells.

FIELD OF THE INVENTION

[0001] The present invention is in the field of devices implantable in abody, and more specifically to implanted devices containing livingcells.

BACKGROUND OF THE INVENTION

[0002] Several disorders arising from hyposecretion of one or moresubstances such as hormones are known. Among these are diabetes,Parkinson's disease, Alzheimer's disease, hypo- and hyper-tension,hypothyroidism, and various liver disorders. The hormone insulin, forexample, is produced by β-cells in the islets of Langerhans of thepancreas. In normal individuals, insulin release is regulated so as tomaintain blood glucose levels in the range of about 70 to 110 milligramsper deciliter. In diabetics, insulin is either not produced at all (Type1 diabetes), or the body cells do not properly respond to the insulinthat is produced (Type 2 diabetes). The result is elevated glucoselevels in the blood.

[0003] Disorders arising from hyposecretion of a hormone are usuallytreated by administration of the missing hormone. However, despiteadvances in understanding and treating many of these diseases, it isoften not possible to precisely regulate metabolism with exogenoushormones. A diabetic, for example, is required to make several dailymeasurements of blood insulin and glucose levels and then inject anappropriate amount of insulin to bring the insulin and glucose levels towithin the acceptable range.

[0004] Organ transplantation is not a viable treatment today for most ofthese disorders for several reasons including rejection of atransplanted organ by the immune system. Isolated cells may be implantedin the body after being treated to prevent rejection. e.g. byimmunosuppression, radiation or encapsulation. Methods ofimmunoprotection of biological materials by encapsulation are disclosedin U.S. Pat. Nos. 4,352,883, 5,427,935, 5,879,709, 5,902,745, and5,912,005. The encapsulating material is selected so as to bebiocompatible and to allow diffusion of small molecules between thecells of the environment while shielding the cells from immunoglobulinsand cells of the immune system. Encapsulated β-cells, for example, canbe injected into a vein (in which case they will eventually becomelodged in the liver) or embedded under the skin, in the abdominalcavity, or in other locations. Fibrotic overgrowth around the implantedcells, however, gradually impairs substance exchange between the cellsand their environment. Hypoxygenation of the cells ultimately leads tocell death.

[0005] U.S. Pat. No. 5,855,613 discloses embedding cells in a thin sheetof alginate gel that is then implanted in a body.

[0006] U.S. Pat. No. 5,834,005 discloses immunoisolating cells byplacing them in a chamber that is implanted inside the body. In thechamber, the cells are shielded from the immune system by means of amembrane permeable to small molecules such as glucose, oxygen, and thehormone secreted by the cells, but impermeable to cells and antibodies.These implanted chambers, however, do not have a sufficiently highsurface area to volume ratio for adequate exchange between the cells andthe blood. Thus, also in this case, hypoxygenation ultimately leads tocell death.

SUMMARY OF THE INVENTION

[0007] The present invention provides an implentable device comprising achamber for holding functional cells and an oxygen generator forproviding oxygen to the cells within the chamber. The cells, referred toherein as “functional cells”, are loaded into the chamber of the devicethat is then implanted in the body. The device comprises an oxygengenerator. i.e. an element that can produce oxygen and make it availableto the cells, so that the functional cells do not suffer fromhypoxygenation. The oxygen generator thus produces oxygen and typicallyreleases the oxygen in the cell's vicinity.

[0008] The chamber has walls, which are permeable to nutrients needed bythe cells as well as substances produced or secreted by the cells, suchsubstances including, for example, metabolites, waste products producedby the cells and substances needed by the individual produced by thefunctional cells. In the body, the functional cells are immunoisolatedfrom body constituents by the chamber's walls while being continuouslyexposed to adequate concentrations of oxygen, nutrients and hormoneswhich penetrate the chamber's walls. The fact that oxygen is supplied tothe cells by the oxygen generator allows the functional cells tomaintain a high metabolic rate, so that a smaller number of functionalcells are required for a given effect, as compared to prior art devices.The device containing the functional cells may be implanted in variousparts of the body such as under the skin or in the peritoneum. Thedevice may have any shape as required by a particular application. Inaccordance with one embodiment of the invention, the device isconfigured as a thin tubular element containing the functional cellwithin the tube's lumen. The device is typically of a size such that itmay be implanted by injection through an introducer such as a syringe.Such an implantation procedure may be short and last only about 10minutes. Other shapes of the device, e.g. a wafer shape, are alsocontemplated within the scope of the invention.

[0009] In one embodiment, the oxygen generator comprises photosyntheticcells that convert carbon dioxide to oxygen when illuminated. Thephotosynthetic cells are preferably unicellular algae, for example, ahigh temperature strain of Chlorella pyrenoidosa (cat. No. 1230. UTEX)having an optimal temperature about equal to body temperature. Otherphotosynthetic cells that may be used with the invention includeChlorella vulgaris, Scenedesmus obligus, Euglena, Volvox, and Spirolina.The photosynthetic cells may be autotrophic or mixotropic. Isolatedchloroplasts may be used instead of, or in addition to, intact cells. Inthe case where the oxygen generator are photosynthetic cells the chambercomprises a light source, with an associated power source, such as abattery. The photosynthetic cells or chloroplasts may be containedwithin a separate compartment within the device, e.g. in the case of adevice in the form of a tube, they may be contained within a thinelongated chamber contained within the tube (in essence a smallerdiameter tube); or may be dispersed.

[0010] In another embodiment, the oxygen generator comprises a pair ofelectrodes. When an electric potential is applied across the electrodes,oxygen is released by electrolysis of ambient water molecules presentwithin the chamber. The electrodes are connected to a power source,typically a rechargeable battery.

[0011] The chamber may further comprise an oxygen sensor that determinesthe oxygen concentration in the vicinity of the functional cells. Amicroprocessor may be provided to turn the oxygen generator when thesensor detects that the oxygen concentration is below a predeterminedminimum and turns it off when the oxygen concentration is above apredetermined maximum.

[0012] The functional cells pancreatic islet cells (α-cells. β-cells,etc.), hepatic cells, neural cells, renal cortex cells, vascularendothelial cells, thyroid cells, parathyroid cells, adrenal cells,adrenal cells, thymic cells ovarian cells, and testicular cells. Inaccordance with one currently preferred embodiment the functional cellsare pancreatic β-cells, which are insulin-releasing cells. Such a devicemay be configured for use in the treatment of insulin-dependent diabetesor for monitoring glucose levels in the body. As another example, thefunctional cells may be hepatic cells, whereby the device can serve asan “artificial liver”.

[0013] The functional cell population in the device may be in the formof individual, may be in the form of cell clusters, or as pieces ofexcised tissue. These tissues or cells include, without limitation,tissue or cells removed from a donor animal, tissue or cells obtained byincubation or cultivation of donor tissues and cells, cells obtainedfrom viable cell lines, cells obtained by genetic engineering. The cellsmay be of human or animal origin as well as genetically engineered orcloned cells or stem cells. The cells may be autologous or heterologouswith the recipient's cells. The tissues or cells may perform a usefulfunction by secreting a beneficial substance into the body, such ashormones or neurotransmitters, or removing a harmful substance from thebody by taking them up, such as in the case of hepatic cells which maytake up various toxic substances. The cells, cell clusters or tissuepieces may be dispersed in a liquid medium or matrix within the chamberor may be attached to a substrate, e.g. the walls of the chamber.

[0014] In another application, the chamber of the present invention isused to implant cells in the body as part of a system for detecting ormonitoring the level of a substance in body fluids. Such a systemcomprises an implentable device of the invention having a detectoradapted to monitor a property of the functional cells that is correlatedwith the level of the substance in the medium surrounding the functionalcells. For example. U.S. Pat. No. 5,101,814, discloses use of a chamberfor implanting glucose sensitive cells into the body and monitoring anoptical or electrical property of the cells that is correlated withglucose levels. The present invention may incorporate a detectorarrangement of the kind disclosed in U.S. Pat. No. 5,101,814.

[0015] The present invention further concerns a method for treating anindividual suffering from a substance-deficiency by implanting in theindividual a device of the invention containing functional cells, whichcan secrete said substance. For example, if the individual suffers frominsulin-dependent (type I) the functional cells may be pancreaticβ-cells.

[0016] By another embodiment the method may employed for treating anindividual suffering from a condition where a beneficial effect may beachieved by removal of a substance from the body, such as in cases of aliver mal-function. The functional cells, in accordance with thisembodiment are capable of removal of such substance.

[0017] The present invention further concerns a method of monitoringlevel of a substance in an individual's body, comprising implanting theabove system in the individual's body and monitoring the reading of saiddetector.

[0018] The power source in the device of the invention is typically arechargeable battery. The device preferably comprises a rechargingcircuitry linked to said batter. For remote induction recharging of thebattery as known per se. The device preferably comprises also anelectronic circuitry for monitoring parameters of the device or itssurrounding or for controlling operational parameters of the device.Such monitored parameters may be parameters influencing the functionalcells' viability or the level of production of a needed substance e.g.the oxygen level; the level of a produced needed substance; the level inbody fluids of a substance which is to be produced or removed by thedevice; etc. The monitored parameters may, for example, be used in orderto control the level of oxygen production (by controlling the current tothe electrodes or the light generated by the light source, as the casemay be). The control circuitry may comprises means for wirelesscommunication with an external device, as known per se.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to understand the invention and to see how it may becarried out in practice, preferred embodiments will now be described, byway of non-limiting examples only, with reference to the accompanyingdrawings, in which:

[0020]FIG. 1 is a device according to a first embodiment of theinvention;

[0021]FIG. 2 is a device according to a second embodiment of theinvention;

[0022]FIG. 3 is a device according to a third embodiment of theinvention: and

[0023]FIG. 4 is a device according to a fourth embodiment of theinvention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0024] First Embodiment

[0025] Referring first to FIG. 1, an embodiment of the device of theinvention, is shown in cross-sectional (FIG. 1a) and longitudinal (FIG.1b) view. The device has a chamber 100 having the overall shape of athin cylinder. The chamber thus has an extremely large surface area tovolume ratio allowing both efficient exchange of nutrients and waste andsimple insertion and retrieval into and out of the peritoneum, or anyother body area. The chamber 100 is flexible and may be made to assumeany desired configuration in the body.

[0026] Outer membrane 105 is formed from a semipermeable material, forexample, a polyvinyl chloride acrylic copolymer. The molecular weightcut-off of the outer membrane 105 is selected so that the outer membrane105 is permeable to nutrients and active substances, such as hormonessecreted by the cells but is impermeable to immunoglobulins and cells.The molecular weight cutoff of the outer membrane 105 is preferablybetween 10,000 and 70,000 Dalton. The outer membrane 105 has ananti-fibrin coating 145 that inhibits fibrotic overgrowth.

[0027] Inner membrane 110 is permeable to small inorganic molecules suchas gases water and salts. The molecular weight cutoff of the innermembrane 110 is preferably between 100 and 200 Dalton. The innermembrane 110 may be made from materials commonly used for artificiallung membranes for example, such materials as are disclosed in U.S. Pat.No. 5,614,378. The interior 130 of inner membrane 110 containsphotosynthetic cells 135. The photosynthetic organisms may be, forexample, unicellular algae such as Chlorella. A light source 140produces light preferably having a wavelength in the range of 400 to 700nm. Light is guided from the light source 140 along the length of thechamber 100 by an optic fiber 148. The chamber 100 contains a powersource-155, a microprocessor 150 that may be for example, a rechargeablebattery or any other kind of power source, and an oxygen sensor 160. Thephotosynthetic cells 135 constitute an oxygen generator.

[0028] Prior to implantation of the chamber 100 into the recipient'sbody, functional cells 120 are loaded into the annular space 115 betweenouter membrane 105 and inner membrane 110. The functional cells 120 maybe, for example, pancreatic islets, in which case about 10 ⁶ islets aresufficient to produce adequate amounts of insulin to regulate glucoselevels in the recipient's body. The functional cells 120 may besuspended in a liquid medium in the annular space 115 or immobilized inthe annular space 115 by embedding in a gel matrix formed, for example,from alginate, polylysine, chitosan, polyvinyl alcohol, polyethyleneglycol, agarose, gelatin, or k-carrageenan.

[0029] After being loaded with the functional cells 120, the chamber 100is implanted into the body by means of an applicator that may be, forexample, a syringe. The processor 150, the light source 140 and thepower source 155 may also be implanted in the body, or may in use beexternal to the body. If the light source 140 in use is external to thebody, the optic fiber 148 is configured to pass through the skin. If theprocessor 150 in use is external to the body, the oxygen sensor 160 isconfigured to pass through the skin.

[0030] When oxygen sensor 160 detects that the oxygen level in theannular space 115 is below a predetermined minimum, the light source 140is turned oil by the microprocessor 150 in order to inducephotosynthesis by the photosynthetic cells 135. The oxygen produced byphotosynthesis in photosynthetic cells 135 is released from thephotosynthetic cells 135 and diffuses through the inner membrane 110into the annular space 115 and is thus made available to the functionalcells 120. When oxygen sensor 160 detects that the oxygen level in theannular space 115 is above a predetermined maximum, the light source 140is turned off by the microprocessor 150 in order to stop photosynthesisby photosynthetic cells 135, so as to conserve the power source 155.About 10⁹-10¹⁰ Chlorella cells are sufficient to produce an adequatesupply of oxygen for 10⁶ functional islets.

[0031] The power source 155 may periodically be recharged when thechamber 100 is inside the body. For example, electrical contacts (notshown) normally located outside the body may be connected via apercutaneous cable to the terminals of the power source 155. An externalvoltage is then applied across the contacts so as to recharge the powersource 155. Alternatively, the power source 155 may be rechargedinductively by applying an electric field externally on the skin in thevicinity of the chamber 100.

[0032] Second Embodiment

[0033] Referring now to FIG. 2, a second embodiment of the invention, isshown in cross-sectional (FIG. 2a) and longitudinal (FIG. 2b) view. Thisembodiment is similar to the first embodiment shown in FIG. 1, andidentical components are identified by the same numeral. A pair offlexible electrodes 315 a and 315 b extends along the length of thechamber 300 in the interior 130 of the inner membrane 110. Theelectrodes are made of a biocompatible material such as carbon orplatinum. The chamber 300 contains a power source 355, a microprocessor350, and an oxygen sensor 160. The electrodes 315 a and 315 b constitutean oxygen generator.

[0034] Prior to insertion of the chamber 300 into the recipient's body,functional cells 120 are loaded into the annular space 115 between outermembrane 105 and inner membrane 110. The functional cells may besuspended in a liquid medium in the annular space 115 or immobilized byembedding the functional cells 120 in a gel matrix formed, for example,from alginate, polylysine, chitosan, polyvinyl alcohol, polyethyleneglycol, agarose, gelatin, or k-carrageenan.

[0035] The chamber 300 is then implanted in the body using an applicatorthat may be, for example, a syringe. The processor 350 and the powersource 355 may also be implanted in the body or may in use be externalto the body. If the processor 350 in use is external to the body, theelectrodes 315 a and 315 b and the oxygen sensor 160 are configured topass through the skin.

[0036] In the body, when oxygen sensor 160 detects that the oxygen levelin the annular space 115 is below a predetermined minimum, themicroprocessor 350 causes an electric potential to be generated betweenthe electrodes 315 a and 315 b by means of the power source 355. Thiscauses hydrolysis of water molecules in the interior 130 of innermembrane 110, producing oxygen. The oxygen molecules diffuse throughinner membrane 110 into the annular space 115 between inner membrane 110and outer membrane 105, and is thus made available to the functionalcells 120. When the oxygen sensor 160 detects that the oxygen level inthe annular space 115 is above a predetermined maximum, the electricalpotential across the electrodes 315 a and 315 b is turned off bymicroprocessor 350, so as to conserve the power source 155. The powersource 155 may be recharged when the chamber 300 is inside the body asdescribed in reference to the previous embodiment.

[0037] Third Embodiment

[0038] In FIG. 3, another embodiment of the invention is shown. Thisembodiment has components in common with the embodiment of FIG. 1 andsimilar components are identified with the same numeral. This embodimenthas a chamber 400 that is formed as a thin planar or wafer-like shapethat is implanted in the body close to the skin 402. The surface 405 ofthe chamber 400 closest to the skin 402 is transparent to light. Thephotosynthetic cells 135 and functional cells 120 are located in theinterior 410 of the chamber 400. The photosynthetic cells 135 areirradiated with light from a light source 415 located outside the body.Light from the light source 415 penetrates through the skin 402 and thesurface 405 to the interior 410 of the chamber 400. The processor 150and the power source 155 may also be implanted in the body or may in usebe located external to the body. The light source 415 may be integralwith the device as shown in FIG. 3a. In this case when the oxygen sensor160 detects that the oxygen level in the interior 410 of the device 400is below a predetermined minimum, the light source 415 is turned on bythe processor 150 in order to induce photosynthesis of thephotosynthetic cells 135. When the oxygen server 160 detects that theoxygen level in the interior 410 is above a predetermined maximum, thelight source 415 is turned off by the processor 150.

[0039] The photosynthetic cells may also be illuminated by a lightsource 415 that is independent of the processor 150 as shown in FIG. 3b.In this case when the oxygen sensor 160 detects that the oxygen level inthe interior 410 of the device 400 is below a predetermined minimum, theprocessor 150 generates a sensible signal such as an audible signalproduced by a loudspeaker 450. This indicates to the individual that hemust irradiate the skin 402 overlying the chamber 400 in order to inducephotosynthesis of the photosynthetic cells 135. When the oxygen sensor160 detects that the oxygen level in the interior 410 is above apredetermined maximum, the processor 450 discontinues the sensiblesignal, thus informing the individual that the illumination should bestopped.

[0040] Fourth Embodiment

[0041] In FIG. 4, yet another embodiment of the invention is shown. Thisembodiment has components in common with the embodiment of FIG. 3 andsimilar components are identified with the same numeral. This embodimenthas a chamber 500 that is formed from a solid gel such as alginate,polylysine, chitosan, polyvinyl alcohol, polyethylene glycol, agarose,gelatin, or k-carrageenan. The gel is preferably transparent to light.The photosynthetic cells 135 and functional cells 120 are embedded inthe gel. The photosynthetic cells 135 are irradiated with light from alight source 415 located outside the body. Light from the light source415 penetrates through the skin 402 and the gel to the photosyntheticcells. The processor 150 and the power source 155 may also be implantedin the body or may in use be located external to the body. The lightsource 415 may be integral with the device as shown in FIG. 4a. In thiscase when the oxygen sensor 160 detects that the oxygen level in theinterior 510 of the device 400 is below a predetermined minimum, thelight source 415 is turned on by the processor 150 in order to inducephotosynthesis of the photosynthetic cells 135. When the oxygen sensor160 detects that the oxygen level in the interior 510 is above apredetermined maximum, the light source 415 is turned off by theprocessor 150.

[0042] The photosynthetic cells may also be illuminated by a lightsource 415 that is independent of the processor 150 as shown in FIG. 4b.In this case when the oxygen sensor 160 detects that the oxygen level inthe interior 510 of the chamber 500 is below a predetermined minimum,the processor 150 generates a sensible signal such as an audible signalproduced by a loudspeaker 450. This indicates to the individual that hemust irradiate the skin 402 overlying the chamber 500 in order to inducephotosynthesis of the photosynthetic cells 135. When the oxygen sensor160 detects that the oxygen level in the interior 410 is above apredetermined maximum, the processor 150 discontinues the sensiblesignal thus informing the individual that the illumination should bestopped.

1. A device implantable in a body comprising a chamber for holdingfunctional cells and an oxygen generator for providing oxygen to thecells within the chamber.
 2. A device according to claim 1 furthercomprising an oxygen sensor for determining oxygen concentration in avicinity of the functional cells.
 3. A device according to claim 2further comprising a microprocessor configured to activate the oxygengenerator when the oxygen concentration in the vicinity of thefunctional cells is below a first predetermined threshold, and toinactivate the oxygen generator when the oxygen concentration in thevicinity of the functional cells is above a second predeterminedthreshold.
 4. A device according to any one of claims 1-3, wherein theoxygen generator comprises one or more photosynthetic cells.
 5. A deviceaccording to claim 4, wherein the photosynthetic cells are algae.
 6. Adevice according to claim 5, wherein the photosynthetic cells areunicellular algae.
 7. A device according to claim 6, wherein theunicellular algae are of the species Chlorella.
 8. A device according toany one of claims 5-7, wherein the algae are genetically engineeredalgae.
 9. A device according to any one of claims 1-3, wherein theoxygen generator comprises isolated chloroplasts.
 10. The deviceaccording to any one of the claims 4 to 9 further comprising a lightsource.
 11. The device according to claim 10 wherein the light source isconfigured to he implanted in the body.
 12. The device according toclaim 11 wherein the light source is configured to be placed external tothe body.
 13. The device according to any one of claims 10 to 12 furthercomprising an optic fiber for conducting light from the light source tothe photosynthetic cells or the chloroplasts.
 14. The device accordingto claim 1 or claim 12 wherein the chamber has transparent walls.
 15. Adevice according to claim 1 wherein the oxygen generator compriseselectrodes for the electrolysis of water molecules to produce oxygen.16. The device according to any one of claims 2 to 15 further configuredto produce a sensible signal when the oxygen concentration is below apredetermined value.
 17. A device according to any one of claims 1-16,wherein the functional cells release a needed substance and the chamberhas walls, which are permeable to said substance but not to said cells,whereby said substance is released to the individual's body.
 18. Adevice according to claim 17, wherein the functional cells are selectedfrom the group consisting of: pancreatic islet cells, hepatocytes,thyroid cells, parathyroid cells, neural cells, ovarian cells, adrenalcells, renal cortex cells, vascular endothelial cells, thymic cells,ovarian cells, testicular cells, genetically engineered cells, clonedcells and stem cells.
 19. A device according to any one of the previousclaims, wherein the functional cells can absorb or degrade a substancefrom an individual's body, and the chamber has walls, which arepermeable to said substance but not to said cells, whereby saidsubstance is drained from the device's surroundings into said chamber.20. A device according to any one of claims 1-19, comprising arechargeable battery.
 21. A device according to claim 20, comprising anelectric circuit linked to said rechargeable battery for remoteinduction recharging of said battery.
 22. A device according to any oneof claims 1-20, comprising an electronic circuitry for monitoringparameters of the device or its surrounding or controlling operationalparameters of the device.
 23. A device according to claim 20, whereinsaid circuitry comprises means for wireless communication with anexternal control or monitoring circuitry
 24. A method of treating anindividual suffering from a substance deficiency, comprising: (a)providing an implentable device having a chamber for holding functionalcells that are capable of secreting said substance, said chamber havingwalls permeable to said substance, and having an oxygen generator forproviding oxygen to the cells: and (b) implanting said device in thebody of the individual.
 25. A method according to claim 24 wherein thefunctional cells are selected from the group consisting of pancreaticislet cells, hepatocytes, thyroid cells, parathyroid cells, neuralcells, ovarian cells, adrenal cells, renal cortex cells, vascularendothelial cells, thymic cells, ovarian cells, and testicular cells.26. A method according to claim 25, for treating diabetes in anindividual wherein the functional cells are insulin secreting cells suchas pancreatic β-cells.
 27. A method of treating an individual sufferingfrom a condition which can be ameliorated by removal of a substance fromthe body comprising: (a) providing an implentable device having achamber for holding functional cells that are capable of absorbing ordegrading said substance, said chamber having walls permeable to saidsubstance, and having an oxygen generator for providing oxygen to thecells: and (b) implanting said device in the body of the individual. 28.A system for monitoring level of a substance in an individual's bodycomprising an implentable device having a chamber for holding functionalcells and a detector adapted to monitor a property of the functionalcells that is correlated with the level of the substance in the mediumsurrounding the cells.
 29. A system according to claim 28, wherein saidcells can react to a substance present in their environment by causing achange in a measurable property, and said detector is adapted to measuresaid measurable quantity.
 30. A method of monitoring a level of asubstance in an individual's body, comprising implanting the system ofclaim 28 or 29 in the individual's body and monitoring the reading ofsaid detector.
 31. A method according to claim 30 for monitoring aglucose level in an individuals body, wherein the functional cells arepancreatic β-cells.